Many biologically active macro-molecules such as peptides/proteins and DNA, effective for gene therapy and a variety of therapeutic applications, have become commercially available through advances in recombinant DNA and other technologies. However, these molecules are limited to parenteral administration due to their susceptibility to degradation in the gastrointestinal tract. Treatment for chronic illnesses or indications may require multiple injections per day over many days, or months. Patient compliance is usually poor. Therefore, it would be highly desirable to develop a system for the delivery of bioactive agents or drugs, in particular, polypeptide or protein drugs, at a controlled rate over a sustained period of time without the above mentioned problems. This system would help to optimize the therapeutic efficacy, minimize the side effects, and thereby improve patient compliance.
Attempts to maintain a steady level of medication using biodegradable polymers have recently attracted considerable attention. These polymers are biodegradable and do not require retrieval after the medication is exhausted. Therefore, they can be fabricated into microspheres, microcapsules or nanospheres with the drug encapsulated in them. Various micro-encapsulation techniques incorporating a bio-active agent into a microparticle carrier are taught in the art, e.g. See U.S. Pat. Nos. 4,652,441; 5,100,669; 4,438,253 and 5,665,428.
However, burst release of the drug is often observed immediately after administration of the microparticle delivering systems. Release of the agent from a microparticle delivery system comprises an initial burst release from the surface of the device. Much higher than normal therapeutic levels of medication in the blood resulting from the burst effect of a microparticle system can cause side effects such as nausea, vomiting, delirium and, sometimes, death. Similar situations can occur when the polymer matrix is catastrophically eroded. Moreover, microparticle dosage forms are not retrievable should an adverse effect occur.
Therefore, it would be desirable to provide a bio-active agent delivery system that reduces "burst release" problem by incorporating the microparticle in a biocompatible, environmentally sensitive polymeric gel matrix. As such, the polymer gel would act as a secondary release barrier for the bio-active agent, reducing the effect of burst release. The microparticle-polymer gel bio-agent delivery system of the present invention provides better control of bio-active agent delivery than either the microparticles or the polymeric gel alone. In addition, since the microparticles are entrapped and localized, retrieval of the microparticel-gel system, if needed, is relatively easy.